Tissue damage leads to pain, which depends on transmission of signals from periphery, through the dorsal horn, and onto the higher centers. Nociception, the detection of painful stimuli, is subject to descending modulation from the brainstem, where direct projections to the spinal cord can have an inhibitory or excitatory effect on dorsal horn neurons. The best-studied modulatory region is the rostral ventromedial medulla (RVM), whose opposing modulatory effects are mediated by two sets of physiologically identified neurons: the ON-cells and the OFF-cells. Firing of ON- and OFF-cells can respectively facilitate or inhibit the passage of nociceptive signals from the periphery. A third set of RVM neurons, the NEUTRAL cells, has a still unclear role in nociceptive modulation. The overarching goal of this proposal is to understand the role of changes in RVM neurons during chronic, inflammatory pain. Using a model of chronic hindpaw inflammation in the rat, this goal will be accomplished through two sets of experiments. Changes in firing of RVM neurons will be studied using single cell recordings and pharmacological manipulation (Specific Aim 1). Immunohistochemistry targeted to activated extracellular signal-related kinase (ERK) will be used to look for changes in transcription, and juxtacellular recording will be used to identify activation of ERK or changes of neurotransmitters in specific cell types (Specific Aim 2). These experiments will advance our understanding of descending modulation in chronic pain and will tie neuronal changes in the RVM to specific physiological cell classes. PUBLIC HEALTH RELEVANCE: Chronic pain is a common symptom of many inflammatory diseases and can persist long after the primary injury has healed. Understanding the underlying mechanisms that initiate and maintain chronic pain will allow us to dissociate the pain from the pathology and to treat the underlying dysfunction instead of just the symptoms. Here the aim is to elucidate how descending modulatory systems could enhance or maintain chronic pain states during persistent inflammation.